Episodic memory includes autobiographical experiences that are consciously recalled as desired. Regions of the medial temporal lobe, including the hippocampus, are generally considered to be the key brain regions controlling episodic memory formation, and the degeneration of these regions, such as during Alzheimer's disease, is often associated with memory loss. Despite memory's important role in both health and disease, little is known about the genetics that determine the differences in memory performance in humans. To identify genetic factors influencing memory we performed a whole-genome association study on individuals of Swiss nationality stratified based upon memory performance. SNP rs17070145, located in the gene KIBRA, was found to be significantly associated with memory performance and was subsequently validated in two independent cohorts. Expression analysis indicated that KIBRA transcripts were enriched in the hippocampus, and functional MRI investigation showed that non-carriers of the rs17070145 T allele increased activation of the hippocampus during memory retrieval. These data suggest a crucial role for KIBRA in episodic memory formation and leads to the hypothesis that a variant of KIBRA exists in individuals with lowered memory performance. The goal of this research plan is to identify this variant and determine its impact on KIBRA. This will be achieved by investigating SNPs of biological relevance on the associated haplotype, identifying those cells in the hippocampus that express KIBRA and compare haplotype negative and positive individuals for differences, by examining in vivo inhibitors of the KIBRA biological pathways for memory modulating affects, and by altering the expression levels of KIBRA within the hippocampus through gene transfer. The proposed studies will lead to a more complete understanding of the biology of memory with the hope of leveraging this information to develop memory-sparing pharmaceuticals for those individuals suffering from amnestic disease. PUBLIC HEALTH RELEVANCE Diseases with memory loss as a symptom are common and devastating. We currently understand very little about how the process of memory works. The goal of this research plan is to expand upon a genetic finding linking a protein known as KIBRA to memory performance to better understand its role in the process of memory with the hopes of not only furthering our knowledge but also developing new drugs to preserve memory function in individuals suffering from amnestic diseases like Alzheimer's. [unreadable] [unreadable]